Substituted phenylamindines, medicaments containing these compounds and process for producing them

ABSTRACT

PCT No. PCT/EP96/01615 Sec. 371 Date Dec. 17, 1997 Sec. 102(e) Date Dec. 17, 1997 PCT Filed Apr. 18, 1996 PCT Pub. No. WO96/33970 PCT Pub. Date Oct. 31, 1996The present invention relates to phenyl amidines of general formula (I), in which R1 to R5 are as defined in claim 1, their tautomers, their stereoisomers and their mixtures and their salts, especially their physiologically acceptable salts with inorganic or organic acids or bases also having valuable pharmacological properties, preferably aggregation-limiting effects, producing them.

This application is a 371 of PCT/EP96/01615, filed Apr. 18, 1996.

The invention relates to phenylamidines of general formula ##STR2## thetautomers thereof, the stereoisomers including the mixtures thereof andthe salts thereof, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases, which have valuablepharmacological properties, preferably aggregation-inhibitingproperties, pharmaceutical compositions containing these compounds, theuse thereof and processes for preparing them.

In the above general formula I

X and Z, which may be identical or different, each denote astraight-chained alkylene group, which may optionally be substituted byone or two alkyl groups, by an alkenyl group having 2 to 4 carbon atoms,by an alkynyl group having 2 to 4 carbon atoms, by an aryl, arylmethyl,heteroaryl or heteroarylmethyl group,

Y denotes a 5- to 7-membered cycloalkylene group optionally substitutedby one or two alkyl groups,

a pyrrolidinylene, piperidinylene or azacycloheptylene group optionallysubstituted by one or two alkyl groups, whilst in the abovementionedrings one or two methylene groups adjacent to a nitrogen atom may bereplaced by a carbonyl group,

a piperazinylene or 1,4-diazacycloheptylene group optionally substitutedby one or two alkyl groups, whilst in the abovementioned rings one ortwo methylene groups adjacent to a nitrogen atom may be replaced by acarbonyl group,

R¹ denotes a hydrogen atom, an alkyl, 1,1,1-trifluoroethyl oralkyloxycarbonyl group, an arylalkyloxycarbonyl group having 1 to 3carbon atoms in the alkyl moiety or a group of formula ##STR3## whereinR^(a) denotes a hydrogen atom or an alkyl group and

R^(b) denotes an alkyl group or a 3- to 7-membered cycloalkyl group,

R² and R³, which may be identical or different, each denote a hydrogen,fluorine, chlorine, bromine or iodine atom, an alkyl, trifluoromethyl oralkoxy group,

R⁴ denotes a hydrogen atom, an alkyl, arylalkyl or heteroarylalkyl groupand

R⁵ denotes a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a4- to 7-membered cycloalkyl group optionally substituted by one or twoalkyl groups, an aryl or arylalkyl group or a group of formula ##STR4##wherein R^(c) denotes a hydrogen atom or an alkyl group,

R^(d) denotes a hydrogen atom or an alkyl group and

R^(e) denotes an alkyl or alkoxy group, a 3- to 7-membered cycloalkylgroup or a 5- to 7-membered cycloalkoxy group,

wherein, unless otherwise stated,

the aryl moieties specified in the definitions of the above groups referto a phenyl group, which may be monosubstituted by R⁶, mono, di- ortrisubstituted by R⁷ or monosubstituted by R⁶ and additionally mono- ordisubstituted by R⁷, wherein the substituents may be identical ordifferent and

R⁶ denotes a cyano, carboxy, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylsulphenyl,alkylsulphinyl, alkylsulphonyl, alkylsulphonyloxy, perfluoralkyl,trifluoromethoxy, nitro, amino, alkylamino, dialkylamino,alkylcarbonylamino, phenylalkylcarbonylamino, phenylcarbonylamino,alkylsulphonylamino, phenylalkylsulphonylamino, phenylsulphonylamino,N-alkyl-alkylcarbonylamino, N-alkyl-phenylalkylcarbonylamino,N-alkyl-phenylcarbonylamino, N-alkyl-alkylsulphonylamino,N-alkyl-phenylalkylsulphonylamino, N-alkyl-phenylsulphonylamino,aminosulphonyl, alkylaminosulphonyl- or dialkylaminosulphonyl group and

R⁷ denotes an alkyl, hydroxy or alkoxy group, a fluorine, chlorine,bromine or iodine atom, wherein two groups R⁶, if they are attached toadjacent carbon atoms, may also denote an alkylene group having 3 to 6carbon atoms, a 1,3-butadiene-1,4-diylene group or a methylenedioxygroup,

the heteroaryl moieties specified in the definitions of the above groupsrefer to a 5-membered heteroaromatic ring, which contains an oxygen,sulphur or nitrogen atom, a nitrogen atom and an oxygen, sulphur ornitrogen atom or two nitrogen atoms and an oxygen, sulphur or nitrogenatom, or a 6-membered heteroaromatic ring, which contains 1, 2 or 3nitrogen atoms and wherein additionally one or two --CH═N-groups mayeach be replaced by an --CO--NR⁸ -group, wherein R⁸ denotes a hydrogenatom or an alkyl group, and additionally the abovementionedheteroaromatic rings may be substituted by one or two alkyl groups ormay also be substituted at the carbon skeleton by a fluorine, chlorine,bromine or iodine atom or by a trifluoromethyl, hydroxy or alkyloxygroup,

and, unless otherwise stated, the abovementioned alkyl, alkylene oralkoxy moieties may each contain 1 to 4 carbon atoms.

However, the preferred compounds of the above general formula I arethose wherein

X denotes a straight-chained alkylene group having 1 to 3 carbon atoms,which may be substituted by one or two alkyl groups, by an alkenyl grouphaving 2 or 3 carbon atoms, by an alkynyl group having 2 or 3 carbonatoms, by a phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,oxazolyl, thiazolyl, 2-imidazolyl, 4-imidazolyl or 5-imidazolyl group,wherein the abovementioned imidazolyl groups may additionally besubstituted by an alkyl group at one of the nitrogen atoms,

Z denotes a methylene or ethylene group, each of which may besubstituted by one or two alkyl groups, by an alkenyl group having 2 or3 carbon atoms, by an alkynyl group having 2 or 3 carbon atoms, by aphenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl,thiazolyl, 2-imidazolyl, 4-imidazolyl or 5-imidazolyl group, wherein theabovementioned imidazolyl groups may additionally be substituted by analkyl group at one of the nitrogen atoms,

Y denotes a cyclohexylene group optionally substituted by one or twoalkyl groups,

a piperidinylene group optionally substituted by one or two alkylgroups, wherein one or two methylene groups adjacent to a nitrogen atommay be replaced by a carbonyl group,

a piperazinylene group optionally substituted by one or two alkylgroups, wherein one or two methylene groups adjacent to a nitrogen atommay be replaced by a carbonyl group,

R¹ denotes a hydrogen atom, an alkyl group, an alkyloxycarbonyl grouphaving a total of 2 to 5 carbon atoms or a phenylmethoxycarbonyl group,

R² denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, atrifluoromethyl group, an alkyl or alkoxy group,

R³ denotes a hydrogen atom,

R⁴ denotes a hydrogen atom or an alkyl group and

R⁵ denotes a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a5- to 7-membered cycloalkyl group or a phenylalkyl group,

the tautomers thereof, the stereoisomers including the mixtures thereofand the salts thereof,

whilst the phenyl groups mentioned in the definitions of the abovegroups may each be mono- or disubstituted by a fluorine, chlorine,bromine or iodine atom, by a methyl, trifluoromethyl, hydroxy or methoxygroup, and the substituents may be identical or different, and thepyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl or thiazolylgroups mentioned in the definitions of the above groups may each besubstituted by a methyl or trifluoromethyl group,

and, unless otherwise stated, the abovementioned alkyl and alkoxymoieties may each contain 1 to 4 carbon atoms.

Particularly preferred are the compounds of general formula ##STR5##wherein X denotes a straight-chained alkylene group having 1 to 3 carbonatoms, which may be substituted by one or two alkyl groups each having 1to 3 carbon atoms, by a vinyl, allyl, ethynyl, propargyl, phenyl,pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group, wherein theabovementioned phenyl group may additionally be substituted by afluorine, chlorine, bromine or iodine atom, by a methyl,trifluoromethyl, hydroxy or methoxy group,

Z denotes a methylene or ethylene group, each of which may besubstituted by one or two alkyl groups each having 1 to 3 carbon atoms,by a vinyl, allyl, ethynyl, propargyl, phenyl, pyridyl, pyrimidinyl,pyridazinyl or pyrazinyl group, wherein the abovementioned phenyl groupmay additionally be substituted by a fluorine, chlorine, bromine oriodine atom, by a methyl, trifluoromethyl, hydroxy or methoxy group,

Y denotes a 1,4-cyclohexylene, 1,4-piperidinylene,2-oxo-1,4-piperidinylene, 1,4-piperazinylene, 2-oxo-1,4-piperazinylene,2,3-dioxo-1,4-piperazinylene or 2,5-dioxo-1,4-piperazinylene group,wherein the abovementioned groups may be substituted by one or two alkylgroups each having 1 to 3 carbon atoms,

R¹ denotes a hydrogen atom, an alkyl group having 1 or 2 carbon atoms,an alkyloxycarbonyl group having a total of 2 or 3 carbon atoms or abenzyloxycarbonyl group,

R² and R³ each denote a hydrogen atom,

R⁴ denotes a hydrogen atom or a methyl group and

R⁵ denotes a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or acyclohexyl group, particularly those compounds wherein

X denotes an ethylene group, which may be substituted by one or twomethyl groups,

Z denotes a methylene group, which may be substituted by one or twomethyl groups, by a pyridyl or phenyl group, wherein the phenyl groupmay additionally be substituted by a fluorine, chlorine or bromine atom,by a methyl, methoxy or trifluoromethyl group,

Y denotes a 1,4-cyclohexylene, 1,4-piperidinylene,2-oxo-1,4-piperidinylene, 1,4-piperazinylene, 2-oxo-1,4-piperazinylene,2,3-dioxo-1,4-piperazinylene or 2,5-dioxo-1,4-piperazinylene group,

R¹ denotes a hydrogen atom, an alkyloxycarbonyl group having a total of2 or 3 carbon atoms or a benzyloxycarbonyl group,

R², R³ and R⁴ each denote a hydrogen atom and R⁵ denotes a hydrogenatom, an alkyl group having 1 to 4 carbon atoms or a cyclohexyl group,

the tautomers thereof, the stereoisomers including the mixtures thereofand the salts thereof.

Most particularly preferred compounds of general formula Ia are thosewherein

X denotes an ethylene group,

Z denotes a methylene group,

Y denotes a 1,4-piperidinylene group,

R¹, R², R³ and R⁴ each denote a hydrogen atom and

R⁵ denotes a hydrogen atom, an alkyl group having 1 or 2 carbon atoms ora cyclohexyl group,

the tautomers thereof, the stereoisomers including the mixtures thereofand the salts thereof.

According to the invention the new compounds of general formula I may beobtained, for example, by the following process:

Reacting a compound of general formula ##STR6## wherein R¹ to R⁴ are ashereinbefore defined, with a compound of general formula ##STR7##wherein R⁵, X, Y and Z are as hereinbefore defined, or the reactivederivatives thereof and

optionally subsequently converting the group R⁵ into a hydrogen atom.

Examples of reactive derivatives of a compound of general formula IIIinclude the acid chlorides, acid azides, mixed anhydrides with aliphaticor aromatic carboxylic acids or monocarboxylates, the imidazolidesthereof and the esters thereof such as the alkyl, aryl and aralkylesters thereof, such as the methyl, ethyl, isopropyl, pentyl, phenyl,nitrophenyl or benzyl ester.

The reaction is conveniently carried out in a solvent or mixture ofsolvents such as methylene chloride, dimethylformamide,dimethylsulphoxide, benzene, toluene, chlorobenzene, tetrahydrofuran,pyridine, pyridine/dimethylformamide, benzene/tetrahydrofuran or dioxaneoptionally in the presence of a dehydrating agent, e.g. in the presenceof isobutyl chloroformate, thionyl chloride, trimethylchlorosilane,sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid,phosphorus trichloride, phosphorus pentoxide,N,N'-dicyclohexylcarbodiimide,N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide,2-(1H-benzotriazolyl)-1,1,3,3-tetramethyl-uronium salts,N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole ortriphenylphosphine/carbon tetrachloride, optionally in the presence ofdimethylaminopyridine or 1-hydroxy-benzotriazole and/or a base such astriethylamine, N-ethyl-diisopropylamine, pyridine orN-methyl-morpholine, conveniently at temperatures between -10 and 180°C., preferably at temperatures between 0 and 120° C.

The subsequent conversion of the group R⁵ into a hydrogen atom isconveniently carried out either in the presence of an acid such ashydrochloric acid, sulphuric acid, phosphoric acid, acetic acid,trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in thepresence of a base such as lithium hydroxide, sodium hydroxide orpotassium hydroxide in a suitable solvent such as water, water/methanol,water/ethanol, water/isopropanol, methanol, ethanol,water/tetrahydrofuran or water/dioxane at temperatures between -10 and120° C., e.g. at temperatures between ambient temperature and theboiling temperature of the reaction mixture.

In the reactions described hereinbefore, any reactive groups presentsuch as carboxy, amino, alkylamino, imino or amidino groups may beprotected during the reaction by conventional protective groups whichare split off again after the reaction.

For example, the protective group for a carboxyl group may be atrimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranylgroup,

the protective group for an optionally alkyl-substituted amidino groupmay be a benzyloxycarbonyl group und

the protective group for an amino, alkylamino or imino group may be aformyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl,benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group,and for the imino group a methyl group may additionally be consideredand for the amino group the phthalyl group is another possibility.

The optional subsequent cleaving of any protective group used may, forexample, by carried out hydrolytically in an aqueous solvent, e.g. inwater, isopropanol/water, acetic acid/water, tetrahydrofuran/water ordioxane/water, in the presence of an acid such as trifluoroacetic acid,hydrochloric acid or sulphuric acid or in the presence of an alkalimetal base such as sodium hydroxide or potassium hydroxide or by ethersplitting, e.g. in the presence of iodotrimethylsilane, at temperaturesbetween 0 and 120° C., preferably at temperatures between 10 and 100° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group ispreferably cleaved by hydrogenolysis, e.g. with hydrogen in the presenceof a catalyst such as palladium/charcoal in a solvent such as methanol,ethanol, ethyl acetate or glacial acetic acid, optionally with theaddition of an acid such as hydrochloric acid at temperatures between 0and 100° C., but preferably at temperatures between 20 and 60° C., andunder a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.However, a 2,4-dimethoxybenzyl group is preferably cleaved intrifluoroacetic acid in the presence of anisol.

A tert.butyl or tert.butyloxycarbonyl group is, however, preferablycleaved by treatment with an acid such as trifluoroacetic acid orhydrochloric acid or by treatment with iodotrimethylsilane, optionallyusing a solvent such as methylene chloride, dioxane, methanol or ether.

However, a trifluoroacetyl group is preferably cleaved by treating withan acid such as hydrochloric acid optionally in the presence of asolvent such as acetic acid or methanol at temperatures between 50 and120° C. or by treating with sodium hydroxide solution optionally in thepresence of a solvent such as tetrahydrofuran or methanol attemperatures between 0 and 50° C.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine such as methylamine, ethylamine or n-butylamine in asolvent such as methanol, ethanol, isopropanol, toluene/water or dioxaneat temperatures between 20 and 50° C.

Moreover, as already mentioned hereinbefore, the compounds of generalformula I obtained may optionally be resolved into their enantiomersand/or diastereomers. Thus, for example, cis/trans mixtures may beresolved into their cis and trans isomers, and compounds with at leastone optically active carbon atom may be resolved into their enantiomers.

Thus, for example, the cis/trans mixtures obtained may be separated intotheir cis and trans isomers by chromatography, the compounds of generalformula I obtained which occur as racemates may be separated into theiroptical antipodes by methods known per se (cf. Allinger N. L. and ElielE. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971))and compounds of general formula I with at least 2 asymmetric carbonatoms may be resolved into their diastereomers on the basis of theirphysical/chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation. If these diastereomersoccur in racemic form they may subsequently be resolved into theenantiomers as described above.

The separation of the enantiomers is preferably carried out by columnseparation on chiral phases or by recrystallisation from an opticallyactive solvent or by reacting with an optically active substance whichforms salts or derivatives such as e.g. esters or amides with theracemic compound, particularly acids and the activated derivatives oralcohols thereof, and separation of the diastereomeric mixture of saltsor derivative thus obtained, e.g. on the basis of differences insolubility, whilst the free antipodes may be released from the purediastereomeric salts or derivatives by the action of suitable agents.Examples of particularly common optically active acids include the D-and L-forms of tartaric acid or dibenzoyltartaric acid,di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonicacid, glutamic acid, aspartic acid or quinic acid. Examples of opticallyactive alcohols include (+) or (-)-menthol and examples of opticallyactive acyl groups in amides include (+)-or (-)-menthyloxycarbonyl.

Moreover, the compounds of formula I obtained may be converted into thesalts thereof, more particularly, for pharmaceutical purposes, thephysiologically acceptable salts thereof with inorganic or organicacids. Examples of suitable acids include hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid,lactic acid, citric acid, tartaric acid or maleic acid.

Furthermore, the new compounds of formula I obtained, if they contain acarboxyl group, may, if desired, subsequently be converted into thesalts thereof with inorganic or organic bases, particularly, forpharmaceutical use, into the physiologically acceptable salts thereof.Examples of bases include sodium hydroxide, potassium hydroxide,arginine, cyclohexylamine, ethanolamine, diethanolamine andtriethanolamine.

The compounds used as starting compounds are known from the literaturein some cases or may be obtained by methods known from the literature(see Examples).

As already mentioned earlier, the new phenylamidines of general formulaI and the salts thereof, particularly the physiologically acceptablesalts thereof with inorganic or organic acids or bases, have valuableproperties. Thus the new compounds of general formula I have valuablepharmacological properties; in addition to an antiinflammatory effectand the effect of inhibiting bone degradation they also have inparticular antithrombotic, antiaggregatory and tumour- andmetastasis-inhibiting effects.

For example, the compounds of general formula I were investigated fortheir biological activities as follows:

1. Inhibiting the Binding of ³ H-BIBU 52 to Human Thrombocytes:

A suspension of human thrombocytes in plasma is incubated with ³ H-BIBU52 =(3S,5S)-5- (4'-amidino-4-biphenylyl)oxymethyl!-3-(carboxy)methyl!-2-pyrrolidinone 3-³ H-4-biphenylyl!!, replacing theligand ¹²⁵ I-fibrinogen known from the literature, (cf. DE-A-4,214.245)and various concentrations of the substance to be tested. The free andbound ligand is separated off by centrifuging and quantitativelydetermined by scintillation counting. From the results obtained, theinhibition of ³ H-BIBU 52 binding by the test substance is determined.

In order to do this, donor blood is taken from an anticubital vein andanticoagulated with trisodium citrate (final concentration 13 mM). Theblood is centrifuged for 10 minutes at 170×g and the supernatantplatelet-rich plasma (PRP) is removed. The residual blood is sharplycentrifuged off once more in order to obtain plasma. The PRP is diluted1:10 with autologous plasma. 750 μl are incubated with 50 μl ofphysiological saline, 100 μl of test substance solution, 50 μl of ¹⁴ Csucrose (3.700 Bq) and 50 μl of ³ H-BIBU 52 (final concentration: 5 nM)at ambient temperature for 20 minutes. In order to measure thenon-specific binding, 5 μl of BIBU 52 (final concentration: 30 μM) areused instead of the test substance. The samples are centrifuged for 20seconds at 10,000×g and the supernatant is removed. 100 μl of it aremeasured in order to determine the free ligand. The pellet is dissolvedin 500 μl of 0.2N NaOH, 450 μl are mixed with 2 ml of scintillator and25 μl of 5N HCl and measured. The residual plasma remaining in thepellet is determined from the ¹⁴ C content, and the bound ligand fromthe measurement of ³ H. After subtracting the non-specific binding thepellet activity is plotted against the concentration of the testsubstance and the concentration for a 50% inhibition of binding isdetermined.

2. Antithrombotic Activity:

Method

The thrombocyte aggregation is measured by the Born and Cross method (J.Physiol. 170, 397 (1964)) in platelet-rich plasma from healthy testsubjects. To inhibit clotting, the blood is mixed with 3.14% sodiumcitrate in a ratio by volume of 1:10.

Collagen-Induced Aggregation

The progress of the decrease in optical density of the plateletsuspension is measured photometrically after the addition of theaggregation-triggering substance and recorded. The rate of aggregationis calculated from the angle of inclination of the density curve. Thepoint on the curve at which there is greatest light permeability is usedto calculate the optical density.

The quantity of collagen is selected to be as small as possible butstill sufficient to produce an irreversible reaction curve. The standardcommercial collagen made by Hormonchemie of Munich is used.

Before the collagen is added, the plasma is incubated with the substanceat 37° C. for 10 minutes.

From the measurements obtained, an EC₅₀ was determined graphicallycorresponding to a 50% change in the optical density in terms ofinhibiting aggregation.

The following Table contains the results found:

    ______________________________________                 .sup.3 H-BIBU-52-                            inhibition of    Substance    binding test                            platelet aggregation    (Example no.)                 IC.sub.50   nM!                            EC.sub.50   nM!    ______________________________________    1            3.7        37    1(1)         51         310    ______________________________________

In view of their inhibitory effect on cell-to-cell and cell-to-matrixinteractions the new cyclic urea derivatives of general formula I andthe physiologically acceptable salts thereof are suitable for combatingor preventing diseases in which smaller or larger cell aggregations areinvolved or cell-to-matrix interactions play a part, e.g. in combatingor preventing venous and arterial thromboses, cerebrovascular diseases,pulmonary embolisms, cardiac infarct, arteriosclerosis, osteoporosis andtumour metastasis and treating genetically caused or acquired disordersof interactions of cells with one another or with solid structures. Theyare also suitable for parallel therapy in thrombolysis withfibrinolytics or vascular interventions such as transluminal angioplastyor in the treatment of shock, psoriasis, diabetes and inflammation.

For combating or preventing the above diseases the dosage is between 0.1μg and 30 mg/kg of body weight, preferably 1 μg to 15 mg/kg of bodyweight, in up to 4 doses per day. For this purpose the compounds offormula I prepared according to the invention, optionally combined withother active substances such as thromboxane-receptor antagonists andthromboxane synthesis inhibitors or combinations thereof, serotoninantagonists, α-receptor antagonists, alkyl nitrates such as glyceroltrinitrate, phosphodiesterase inhibitors, prostacyclin and the analoguesthereof, fibrinolytics such as tPA, prourokinase, urokinase,streptokinase, or anticoagulants such as heparin, dermatan sulphate,activated protein C, vitamin K antagonists, hirudine, inhibitors ofthrombin or other activated clotting factors, together with one or moreinert conventional carriers and/or diluents, e.g. with corn starch,lactose, glucose, microcrystalline cellulose, magnesium stearate,polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethyleneglycol,propyleneglycol, stearyl alcohol, carboxymethylcellulose or fattysubstances such as hard fat or suitable mixtures thereof, may beincorporated in conventional galenic preparations such as plain orcoated tablets, capsules, powders, suspensions, solutions, sprays orsuppositories.

The Examples which follow are intended to illustrate the invention morefully:

EXAMPLE I 4- 2-(chlorocarbonyl)ethyl!-1-(ethoxycarbonyl)methyl!-piperidine-hydrochloride

To 1.46 g of 4-(2-carboxyethyl)-1- (ethoxycarbonyl)methyl!-piperidine in10 ml methylene chloride, is added 1 ml of saturated etherealhydrochloric acid. 1.2 g of thionyl chloride are added and the mixtureis stirred for 3 hours at ambient temperature. The reaction mixture isconcentrated by evaporation and the residue is mixed twice with tolueneand evaporated down again. The crude product is further reacted inExamples 1 and 2 without being purified.

The following compounds are obtained analogously to Example I:

(1) 1- 2-(chlorocarbonyl)ethyl!-4-(methoxycarbonyl)methyl!-piperidine-hydrochloride

(2) 4- 2-(chlorocarbonyl)ethyl!-1-(cyclohexyloxycarbonyl)methyl!-piperidine-hydrochloride

EXAMPLE II 4- 2-(carboxy)ethyl!-1- (ethoxycarbonyl)methyl!-piperidine

10 g of 4- 2-(benzyloxycarbonyl)ethyl!-1-(ethoxycarbonyl)methyl!-piperidine are hydrogenated in 150 ml oftetrahydrofuran for 4 hours at ambient temperature under a hydrogenpressure of 50 psi in the presence of 1.3 g of palladium on activatedcharcoal. The reaction mixture is evaporated down and crystallised fromdiethylether and a little acetone.

yield: 5.8 g of (79% of theory), melting point: 65-67° C.

The following compound is obtained analogously to Example II:

(1) 4-(2-carboxyethyl)-1- (cyclohexyloxycarbonyl)methyl!-piperidine

melting point: 85-88° C.

EXAMPLE III 4- 2-(benzyloxycarbonyl)ethyl!-1-(ethoxycarbonyl)methyl!-piperidine

To 9.0 g of 4- 2-(benzyloxycarbonyl)ethyl!-piperidine and 5.2 g ofN-ethyl-diisopropylamine in 70 ml of acetonitrile, 6.35 g of ethylbromoacetate in 20 ml of acetonitrile are added dropwise with stirringin an ice bath and the mixture is stirred for 18 hours at ambienttemperature. The reaction mixture is concentrated by evaporation and theresidue is quickly divided between tert.butyl-methylether, ice water and10 ml of 2N sodium hydroxide solution. The organic phase is separatedoff, washed with ice water and saturated saline solution, dried andconcentrated by evaporation.

yield: 10.05 g of (83% of theory), R_(f) value: 0.84 (silica gel;methylene chloride/methanol/conc. aqueous ammonia=95:5:1).

The following compound is obtained analogously to Example III:

(1) 4- 2-(benzyloxycarbonyl)ethyl!-1-(cyclohexyloxycarbonyl)methyl!-piperidin

R_(f) value: 0.47 (silica gel; methylene chloride/methanol/conc. aqueousammonia=98:2:0,5).

EXAMPLE IV 4- 2-(benzyloxycarbonyl)ethyl!-piperidine

9.7 g of 4-(2-carboxyethyl)piperidine-hydrochloride (melting point:240-250° C., prepared by hydrogenation of 3-(4-pyridyl)acrylic acid inglacial acetic acid in the presence of platinum oxide and subsequenttreatment with hydrochloric acid), 30 ml of benzyl alcohol, 3 g ofp-toluenesulphonic acid and 50 ml of toluene are heated for 75 minutesusing the water separator. The reaction mixture is concentrated byevaporation in vacuo, the residue is mixed with 50 ml of ice water andextracted three times with tert.butyl-methylether. The aqueous phase ismade alkaline and extracted with tert.butyl-methylether. The extract iswashed with saline solution, dried and concentrated by evaporation.

yield: 9.0 g (73% of theory), R_(f) value: 0.18 (silica gel; methylenechloride/methanol/conc. aqueous ammonia=95:5:1).

EXAMPLE V 1-(2-carboxyethyl)-4-(methoxycarbonyl)methyl!-piperidine-hydrochloride

To 2.9 g of 1- 2-(tert.butoxycarbonyl)ethyl!-4-(methoxycarbonyl)-methyl!-piperidine in 20 ml of methylene chloride areadded 10 ml of trifluoroacetic acid and the mixture is stirred overnightat ambient temperature. The reaction mixture is concentrated byevaporation, taken up in acetone, mixed with ethereal hydrochloric acidand again concentrated by evaporation. It is once more taken up inacetone, mixed with ethereal hydrochloric acid and concentrated byevaporation. The residue is stirred with tert.butyl-methylether, towhich some acetone has been added, suction filtered and dried.

yield: 2,45 g (92% of theory), R_(f) value: 0.73 (reversed phase silicagel; methanol/5% aqueous saline solution=6:4).

EXAMPLE VI 1- 2-(tert.butoxycarbonyl)ethyl!-4-(methoxycarbonyl)methyl!-piperidine

A mixture of 9 ml of tert.butyl acrylate, 10 g of 4-(methoxycarbonyl)methyl!-piperidine-hydrochloride and 7.2 ml oftriethylamine in 150 ml of methanol is refluxed overnight. The reactionmixture is concentrated by evaporation, taken up in methylene chlorideand washed twice with saturated sodium hydrogen carbonate solution. Theorganic phase is separated off, concentrated by evaporation and theresidue is purified by chromatography over a silica gel column withmethylene chloride/methanol (35:5).

yield: 12.6 g (86% of theory), R_(f) value: 0.68 (silica gel; methylenechloride/methanol=9:1).

EXAMPLE 1 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-carboxymethyl-piperidine.times.0.2H₂ O

To 420 mg of 4-aminobenzamidine-dihydrochloride and 20 mg of4-dimethylaminopyridine in a mixture of 1.5 ml of dimethylformamide and1.5 ml of pyridine are added 720 mg of 4- 2-(chlorocarbonyl)ethyl!-1-(ethoxycarbonyl)methyl!-piperidine-hydrochloride and the mixture isstirred for 1.3 hours at 100° C. The reaction mixture is cooled, mixedwith ice water, made alkaline with sodium hydroxide solution andextracted with tert.butyl-methylether and methylene chloride. Theaqueous phase is adjusted with hydrochloric acid to a pH value of 3-4and evaporated to dryness at a bath temperature of 70° C. The residue isheated to boiling with 100 ml of ethanol, after cooling it is filteredand the filtrate is concentrated by evaporation. The evaporation residueis heated with 30 ml of ethanol, it is cooled and the solid is suctionfiltered. The solid is stirred with 15 ml of tetrahydrofuran and 4.5 mlof 1N sodium hydroxide solution. The mixture is combined with 2.75 ml of1N hydrochloric acid and stirred over an ice bath. The precipitate iswashed with water and tetrahydrofuran and dried in vacuo.

yield: 144 mg (21% of theory), melting point: 283° C. (decomp.). R_(f)value: 0.76 (reversed phase silica gel; methanol/5% aqueous salinesolution=6:4) Calculated: C 60.77, H 7.32, N 16.67 Found: 60.55, 7.26,16.83 Mass spectrum: (M+H)⁺ =333.

The following compounds are obtained analogously to Example 1:

(1) 1- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-4-carboxymethyl-piperidine.times.2H₂ O

melting point: 192-200° C. (with sintering and decomposition). R_(f)value: 0,77 (reversed phase silica gel; methanol/5% aqueous salinesolution=6:4) Calculated: C 55.42, H 7.66, N 15.21 Found: 55.02, 7.38,14.95

(2) 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-carboxymethyl-piperazine

(3) 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-carboxymethyl-2-oxo-piperidine

(4) 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-carboxymethyl-2-oxo-piperazine

(5) 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-carboxymethyl-3-methyl-2-oxo-piperazine

(6) 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-carboxymethyl-2,3-dioxo-piperazine

(7) 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-carboxymethyl-2,5-dioxo-piperazine

(8) 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-carboxymethyl-3-oxo-piperazine

(9) 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-carboxymethyl-cyclohexane

(10) 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-(1-carboxyethyl)-piperidine

(11) α- 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-piperidinyl!-phenylacetic acid

(12) α- 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-piperidinyl!-(3-pyridyl)aceticacid

(13) 4- 2-(4-amidinophenyl)aminocarbonyl!propyl!-1-carboxymethyl-piperidine

(14) 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-carboxymethyl-3,3-dimethyl-2-oxo-piperazine

(15) α- 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-piperidinyl!-(4-fluorophenyl)aceticacid

(16) α- 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-piperidinyl!-(4-methoxyphenyl)aceticacid

(17) 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-(2-carboxyethyl)-piperidine

EXAMPLE 2 4- 2- (4-amidinophenyl)aminocarbonyl!ethyl!-1-(ethoxycarbonyl)methyl!-piperidine×2,15 HCl×0.7 H₂ O

To 625 mg of 4-aminobenzamidine and 30 mg of 4-dimethylaminopyridine in5 ml of pyridine are added 950 mg of 4- 2-(chlorocarbonyl)ethyl!-1-(ethoxycarbonyl)methyl!-piperidine-hydrochloride and the mixture isstirred for 1 hour at 100° C. 2 ml of dimethylformamide are added andthe mixture is stirred for a further 1.2 hours at 100° C. The reactionmixture is concentrated by evaporation and the residue is stirred twicewith tert.butyl-methylether, the solvent being decanted off anddiscarded each time. The residue is purified by chromatography overaluminium oxide with ethanol. The product is dissolved in ethanol, madeslightly acidic with ethereal hydrochloric acid and concentrated byevaporation. The residue is triturated with acetone, the solid issuction filtered and dried.

yield: 335 mg of (25% of theory), R_(f) value: 0.35 (aluminium oxide;ethanol/conc. aqueous ammonia=99:1) Calculated: C 50.55, H 7.04, N12.41, Cl 16.88 Found: 50.02, 6.96, 12.51, 17.27 Mass spectrum: (M+H)⁺=361.

The hydrochlorides of the following compounds are obtained analogouslyto Example 2:

(1) 1- 2- (4-amidinophenyl)aminocarbonyl!ethyl!-4-(ethoxycarbonyl)methyl!-piperidine

(2) 4- 2- (4-amidinophenyl)aminocarbonyl!ethyl!-1-(ethoxycarbonyl)methyl!-piperazine

(3) 4- 2- (4-amidinophenyl)aminocarbonyl!ethyl!-1-(ethoxycarbonyl)methyl!-2-oxo-piperidine

(4) 4- 2- (4-amidinophenyl)aminocarbonyl!ethyl!-1-(ethoxycarbonyl)methyl!-2-oxo-piperazine

(5) 4- 2- (4-amidinophenyl)aminocarbonyl!ethyl!-1-(ethoxycarbonyl)methyl!-3-methyl-2-oxo-piperazine

(6) 4- 2- (4-amidinophenyl)aminocarbonyl!ethyl!-1-(ethoxycarbonyl)methyl!-2,3-dioxo-piperazine

(7) 4- 2- (4-amidinophenyl)aminocarbonyl!ethyl!-1-(ethoxycarbonyl)methyl!-2,5-dioxo-piperazine

(8) 4- 2- (4-amidinophenyl)aminocarbonyl!ethyl!-1-(ethoxycarbonyl)methyl!-3-oxo-piperazine

(9) 4- 2- (4-amidinophenyl)aminocarbonyl!ethyl!-1-(ethoxycarbonyl)methyl!-cyclohexane

(10) 4- 2- (4-amidinophenyl)aminocarbonyl!ethyl!-1-1-(ethoxycarbonyl)ethyl!-piperidine

(11) ethyl α- 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-piperidinyl!-phenylacetate

(12) ethyl α- 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-piperidinyl!-(3-pyridyl)acetate

(13) 4- 2- (4-amidinophenyl)aminocarbonyl!propyl!-1-(ethoxycarbonyl)methyl!-piperidine

(14) 4- 2- (4-amidinophenyl)aminocarbonyl!ethyl!-1-(ethoxycarbonyl)methyl!-3,3-dimethyl-2-oxo-piperazine

(15) ethyl α- 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-piperidinyl!-(4-fluorophenyl)acetate

(16) ethyl α- 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-piperidinyl!-(4-methoxyphenyl)acetate

(17) 4- 2- (4-amidinophenyl)aminocarbonyl!ethyl!-1-2-(ethoxycarbonyl)ethyl!-piperidine

(18) 4- 2- (4-amidinophenyl)aminocarbonyl!ethyl!-1-(cyclohexyloxycarbonyl)methyl!-piperidine×2,3 HCl×2 H₂ O

melting point: from 170° C. (decomp.). R_(f) value: 0.58 (reversed phasesilica gel; methanol/5% aqueous saline solution=6:4) Calculated: C51.69, H 7.60, N 10.48, Cl 15.26 Found: 51.69, 7.46, 10.44, 15.17

EXAMPLE 3 Dry Ampoule Containing 2.5 mg of Active Substance per 1 ml

    ______________________________________    Composition:    ______________________________________    active substance      2.5     mg    mannitol              50.0    mg    water for injections  ad 1.0  ml    ______________________________________

Method of Preparation:

The active substance and mannitol are dissolved in water. Afterbottling, the solution is freeze-dried. For use, the solution is made upwith water for injections.

EXAMPLE 4 Dry Ampoule Containing 35 mg of Active Substance per 2 ml

    ______________________________________    Composition:    ______________________________________    active substance      35.0    mg    mannitol              100.0   mg    water for injections  ad 2.0  ml    ______________________________________

Method of Preparation:

The active substance and mannitol are dissolved in water. Afterpackaging, the solution is freeze-dried. For use, the solution is madeup with water for injections.

EXAMPLE 5 Tablet Containing 50 mg of Active Substance

    ______________________________________    Composition:    ______________________________________    (1) active substance   50.0   mg    (2) lactose            98.0   mg    (3) maize starch       50.0   mg    (4) polyvinylpyrrolidone                           15.0   mg    (5) magnesium stearate 2.0    mg                           215.0  mg    ______________________________________

Method of Preparation:

(1), (2) and (3) are mixed together and granulated with an aqueoussolution of (4). (5) is added to the dry granulate. From this mixturecompressed tablets are produced, which are biplanar, faceted on bothsides and provided with a dividing notch on one side.

Diameter of the tablets: 9 mm.

EXAMPLE 6 Tablet Containing 350 mg of Active Substance

    ______________________________________    Composition:    ______________________________________    (1) active substance   350.0  mg    (2) lactose            136.0  mg    (3) maize starch       80.0   mg    (4) polyvinylpyrrolidone                           30.0   mg    (5) magnesium stearate 4.0    mg                           600.0  mg    ______________________________________

Method of Preparation:

(1), (2) and (3) are mixed together and granulated with an aqueoussolution of (4). (5) is added to the dry granulate. From this mixturecompressed tablets are produced, which are biplanar, faceted on bothsides and provided with a dividing notch on one side.

Diameter of the tablets: 12 mm.

EXAMPLE 7 Capsules Containing 50 mg of Active Substance

    ______________________________________    Composition:    ______________________________________    (1) active substance   50.0   mg    (2) dried maize starch 58.0   mg    (3) powdered lactose   50.0   mg    (4) magnesium stearate 2.0    mg                           160.0  mg    ______________________________________

Method of Preparation:

(1) is triturated with (3). This triturated mixture is added to thecombination of (2) and (4) with thorough blending.

Using a capsule filling machine this powdered mixture is packed intosize 3 hard gelatin capsules.

EXAMPLE 8 Capsules Containing 350 mg of Active Substance

    ______________________________________    Composition:    ______________________________________    (1) active substance   350.0  mg    (2) dried maize starch 46.0   mg    (3) powdered lactose   30.0   mg    (4) magnesium stearate 4.0    mg                           430.0  mg    ______________________________________

Method of Preparation:

(1) is triturated with (3). This triturated mixture is added to thecombination of (2) and (4) with thorough blending.

Using a capsule filling machine this powdered mixture is packed intosize 0 hard gelatin capsules.

We claim:
 1. A phenylamidine of formula ##STR8## wherein X and Z, whichmay be identical or different, each denote a straight-chained alkylenegroup, which may optionally be substituted by one or two alkyl groups,by an alkenyl group having 2 to 4 carbon atoms, by an alkynyl grouphaving 2 to 4 carbon atoms, by an aryl, arylmethyl, heteroaryl orheteroarylmethyl group,Y denotes an optionally by one or two alkylgroups substituted piperidinylene, 2-oxo-piperidinylene or 2,6-dioxopiperidinylene group, R¹ denotes a hydrogen atom, an alkyl,1,1,1-trifluoroethyl or alkyloxycarbonyl group, an arylalkyloxycarbonylgroup having 1 to 3 carbon atoms in the alkyl moiety or a group offormula ##STR9## wherein R^(a) denotes a hydrogen atom or an alkyl groupand R^(b) denotes an alkyl group or a 3- to 7-membered cycloalkyl group,R² and R³, which may be identical or different, each denote a hydrogen,fluorine, chlorine, bromine or iodine atom, an alkyl, trifluoromethyl oralkoxy group, R⁴ denotes a hydrogen atom, an alkyl, arylalkyl orheteroarylalkyl group and R⁵ denotes a hydrogen atom, an alkyl grouphaving 1 to 8 carbon atoms, a 4- to 7-membered cycloalkyl groupoptionally substituted by one or two alkyl groups, an aryl or arylalkylgroup or a group of formula ##STR10## wherein R^(c) denotes a hydrogenatom or an alkyl group, R^(d) denotes a hydrogen atom or an alkyl groupand R^(e) denotes an alkyl or alkoxy group, a 3- to 7-memberedcycloalkyl gorup or a 5- to 7-membered cycloalkoxy group,wherein, unlessotherwise stated, the aryl moieties specified in the definitions of theabove groups refer to a phenyl group, which may be monosubstituted byR⁶, mono, di- or trisubstituted by R⁷ or monosubstituted by R⁶ andadditionally mono- or disubstituted by R⁷, wherein the substituents maybe identical or different and R⁶ denotes a cyano, carboxy,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonyl,alkylcarbonyl, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl,alkylsulphonyloxy, perfluoralkyl, trifluoromethoxy, nitro, amino,alkylamino, dialkylamino, alkylcarbonylamino, phenylalkylcarbonylamino,phenylcarbonylamino, alkylsulphonylamino, phenylalkylsulphonylamino,phenylsulphonylamino, N-alkyl-alkylcarbonylamino,N-alkyl-phenylalkylcarbonylamino, N-alkyl-phenylcarbonylamino,N-alkyl-alkylsulphonylamino, N-alkyl-phenylalkylsulphonylamino,N-alkyl-phenylsulphonylamino, aminosulphonyl, alkylaminosulphonyl- ordialkylaminosulphonyl group and R⁷ denotes an alkyl, hydroxy or alkoxygroup, a fluorine, chlorine, bromine or iodine atom, wherein two groupsR⁷, if they are attached to adjacent carbon atoms, may also denote analkylene group having 3 to 6 carbon atoms, a 1,3-butadiene-1,4-diylenegroup or a methylenedioxy group, the heteroaryl moieties specified inthe definitions of the above groups refer to a 5-membered heteroaromaticring, which contains an oxygen, sulphur or imino group, a nitrogen atomand an oxygen, sulphur or imino group or two nitrogen atoms and anoxygen, sulphur or imino group, or a 6-membered heteroaromatic ring,which contains 1, 2 or 3 nitrogen atoms and wherein additionally one ortwo --CH═N-groups may each be replaced by an --CO--NR⁸ -group, whereinR⁸ denotes a hydrogen atom or an alkyl group, and additionally the abovementioned heteroaromatic rings may be substituted by one or two alkylgroups or may also be substituted at the carbon skeleton by a fluorine,chlorine, bromine or iodine atom or by a trifluoromethyl, hydroxy oralkyloxy group, and, unless otherwise stated, the above mentioned alkyl,alkylene or alkoxy moieties may each contain 1 to 4 carbon atoms atautomer thereof, a stereoisomer including a mixture thereof or a saltthereof.
 2. The phenylamidine of formula I as recited in claim 1,whereinX denotes a straight-chained alkylene group having 1 to 3 carbonatoms, which may be substituted by one or two alkyl groups, by analkenyl group having 2 or 3 carbon atoms, by an alkynyl group having 2or 3 carbon atoms, by a phenyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, oxazolyl, thiazolyl, 2-imidazolyl, 4-imidazolyl or5-imidazolyl group, wherein the above mentioned imidazolyl groups mayadditionally be substituted by an alkyl group at one of the nitrogenatoms, Z denotes a methylene or ethylene group, each of which may besubstituted by one or two alkyl groups, by an alkenyl group having 2 or3 carbon atoms, by an alkynyl group having 2 or 3 carbon atoms, by aphenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl,thiazolyl, 2-imidazolyl, 4-imidazolyl or 5-imidazolyl group, wherein theabove mentioned imidazolyl groups may additionally be substituted by analkyl group at one of the nitrogen atoms, Y denotes an optionally by oneor two alkyl groups substituted piperidinylene, 2-oxo-piperidinylene or2,6-dioxo-piperidinylene group, R¹ denotes a hydrogen atom, an alkylgroup, an alkyloxycarbonyl groups having a total of 2 to 5 carbon atomsor a phenylmethoxycarbonyl group, R² denotes a hydrogen, fluorine,chlorine, bromine or iodine atom, a trifluoromethyl group, an alkyl oralkoxy group, R³ denotes a hydrogen atom, R⁴ denotes a hydrogen atom oran alkyl group and R⁵ denotes a hydrogen atom, an alkyl group having 1to 8 carbon atoms, a 5- to 7-membered cycloalkyl group or a phenylalkylgroup, whilst the phenyl groups mentioned in the definitions of theabove groups may each be mono- or disubstituted by a fluorine, chlorine,bromine or iodine atom, by a methyl, trifluoromethyl, hydroxy or methoxygroup, and the substituents may be identical or different, and thepyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl or thiazolylgroups mentioned in the definitions of the above groups may each besubstituted by a methyl or trifluoromethyl group, and, unless otherwisestated, the above mentioned alkyl and alkoxy moieties may each contain 1to 4 carbon atoms, a tautomer thereof, a stereoisomer including amixture thereof or a salt thereof.
 3. The phenylamidine as recited inclaim 2, whereinY denotes an optionally by one or two C₁₋₄ -alkyl groupssubstituted piperidinylene group, a tautomer thereof, a stereoisomerincluding a mixture thereof or a salt thereof.
 4. A phenylamidine offormula ##STR11## wherein X denotes a straight-chained alkylene grouphaving 1 to 3 carbon atoms, which may be substituted by one or two alkylgroups each having 1 to 3 carbon atoms, by a vinyl, allyl, ethynyl,propargyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group,wherein the above mentioned phenyl group may additionally be substitutedby a fluorine, chlorine, bromine or iodine atom, by a methyl,trifluoromethyl, hydroxy or methoxy groups,Z denotes a methylene orethylene group, each of which may be substituted by one or two alkylgroups each having 1 to 3 carbon atoms, by a vinyl, allyl, ethynyl,propargyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinylgroups, wherein the above mentioned phenyl group may additionally besubstituted by a fluorine, chlorine, bromine or iodine atom, by amethyl, trifluoromethyl, hydroxy or methoxy group, Y denotes anoptionally by one or two C₁₋₃ -alkyl groups substituted piperidinylenegroup, R¹ denotes a hydrogen atom, an alkyl group having 1 or 2 carbonatoms, an alkyloxycarbonyl group having a total of 2 or 3 carbon atomsor a benzyloxycarbonyl group, R² and R³ each denote a hydrogen atom, R⁴denotes a hydrogen atom or a methyl group and R⁵ denotes a hydrogenatom, an alkyl group with 1 to 4 carbon atoms or a cyclohexyl group, atautomer thereof, a stereoisomer including a mixture thereof or a saltthereof.
 5. The phenylamidine of formula Ia as recited in claim 4,whereinX denotes an ethylene group, which may be substituted by one ortwo methyl groups, Z denotes a methylene group, which may be substitutedby one or two methyl groups, by a pyridyl or phenyl group, wherein thephenyl group may additionally be substituted by a fluorine, chlorine orbromine atom, by a methyl, methoxy or trifluoromethyl group, Y denotes a1, 4-piperidinylene group, R¹ denotes a hydrogen atom, analkyloxycarbonyl group having a total of 2 or 3 carbon atoms or abenzyloxycarbonyl group, R², R³ and R⁴ each denote a hydrogen atom andR⁵ denotes a hydrogen atom, an alkyl group having 1 to 4 carbon atoms ora cyclohexyl group, a tautomer thereof, a stereoisomer including amixture thereof or a salt thereof.
 6. The phenylamidine of formula Ia asrecited in claim 4, whereinX denotes an ethylene group, Z denotes amethylene group, Y denotes a 1,4-piperidinylene group, R¹, R², R³ and R⁴each denote a hydrogen atom and R⁵ denotes a hydrogen atom, an alkylgroup having 1 or 2 carbon atoms or a cyclohexyl group, a tautomerthereof, a stereoisomer including a mixture thereof or a salt thereof.7. The phenylamidine of formula I as recited in claim 1, which is4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-carboxymethyl-piperidine, 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-(ethoxycarbonyl)-methyl!-piperidine or 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-(cyclohexyl-oxycarbonyl)methyl!-piperidine or a salt thereof.
 8. 4- 2-(4-amidinophenyl)aminocarbonyl!ethyl!-1-carboxymethyl-piperidine or asalt thereof.
 9. The physiologically acceptable salt of thephenylamidine as recited in claim 1 with an inorganic or organic acid orbase.
 10. A pharmaceutical composition of matter comprising aphenylamidine as recited in claim 1 together with one or more inertcarriers or diluents.
 11. A method for treating or preventing disease ina warm-blooded animal in which smaller or larger cell aggregation occursor cell-matrix interaction plays a role which comprises administering tothe animal a therapeutically effective amount of a phenylamidine asrecited in claim 1.